Dissolving microneedles-based programmed delivery system for enhanced chemo-immunotherapy of melanoma.

Immune checkpoint blockade, especially the programmed cell death ligand 1 (PD-L1) blockade, has revolutionized the treatment of melanoma. However, PD-1/PD-L1 monotherapy leads to unsatisfactory therapeutic outcomes. The immunotherapy of melanoma could be improved by adding doxorubicin (DOX), which triggers immunogenic cell death (ICD) effect to activate anti-tumor immunity. Additionally, microneedles, especially dissolving microneedles (dMNs), can further enhance outcomes of chemo-immunotherapy due to the physical adjuvant effect of dMNs. Herein, we developed the dMNs-based programmed delivery system that incorporated pH-sensitive and melanoma-targeting liposomes to co-deliver DOX and siPD-L1, achieving enhanced chemo-immunotherapy of melanoma (si/DOX@LRGD dMNs). The incorporated si/DOX@LRGD LPs demonstrated uniform particle size, pH-sensitive drug release, high in vitro cytotoxicity and targeting ability. Besides, si/DOX@LRGD LPs effectively downregulated the expression of PD-L1, induced tumor cell apoptosis and triggered ICD effect. The si/DOX@LRGD LPs also showed deep penetration (approximately 80 µm) in 3D tumor spheroids. Moreover, si/DOX@LRGD dMNs dissolved rapidly into the skin and had sufficient mechanical strength to penetrate skin, reaching a depth of approximately 260 µm in mice skin. In mice model of melanoma tumor, si/DOX@LRGD dMNs exhibited better anti-tumor efficacy than monotherapy by dMNs and tail intravenous injection at the same dose. This was due to the higher cytotoxic CD8+ T cells and the secreted cytotoxic cytokine IFN-γ evoked by si/DOX@LRGD dMNs, thereby eliciting strong T-cell mediated immune response and resulted in enhanced anti-tumor effects. In conclusion, these findings suggested that si/DOX@LRGD dMNs provided a promising and effective strategy for enhanced chemo-immunotherapy of melanoma.

Nano-ultrasonic Contrast Agent for Chemoimmunotherapy of Breast Cancer by Immune Metabolism Reprogramming and Tumor Autophagy.

The functional status of innate immune cells is a considerable determinant of effective antitumor immune response. However, the triple-negative breast cancer tumor microenvironment with high lactic acid metabolism and high antioxidant levels limits immune cell survival, differentiation, and function. Here, we determine that the tumor microenvironment-responsive nano-ultrasonic contrast agent Pt(IV)/CQ/PFH NPs-DPPA-1 boosts the ratio of mature dendritic cells (mDCs) and proinflammatory macrophages by reprogramming the metabolism of immature DCs (iDCs) and tumor-associated macrophages (TAMs). Specifically, platinum(IV) in cancer cells or iDCs was reduced to cisplatin, which can increase the intracellular content of ROS and therefore enhance the ratio of mDCs and apoptotic tumor cells. Meanwhile, chloroquine (CQ) released from nanoparticles (NPs) minimizes protective autophagy caused by cisplatin in tumor cells and reprograms the metabolism of TAMs to enhance the proportion of proinflammatory macrophages, achieving a superior synergistic effect of chemoimmunotherapy combined with Pt(IV) and anti-PD-L1 peptide (DPPA-1). Furthermore, perfluorohexane (PFH) in NPs realizes monitoring treatment corresponding to ultrasound. Collectively, the nano-ultrasonic contrast agent supports a candidate for monitoring treatment and augmenting antitumor chemoimmunotherapy by suppressing tumor cell autophagy and reprogramming immunocyte metabolism.

Effects of continuous positive airway pressure on plasma fibrinogen levels in obstructive sleep apnea patients: a systemic review and meta-analysis.

OBJECTIVE: Fibrinogen has been implicated to play a role in the pathophysiology of obstructive sleep apnea (OSA). Many studies have evaluated the effect of continuous positive airway pressure (CPAP) on plasma fibrinogen levels in OSA patients. However, results from different reports were not consistent. To assess the effect of CPAP treatment on plasma fibrinogen levels of patients with OSA, a meta-analysis was performed. METHODS: A systematic search of Pubmed, Embase, Cochrane, Wanfang Database and Chinese National Knowledge Infrastructure was performed. Data were extracted, and then weighted mean difference (WMD) and 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS: Twenty-two studies involving 859 patients were included in this meta-analysis. Combined data showed that plasma fibrinogen concentrations decreased after CPAP therapy (WMD = -0.38 g/l, 95% CI [-0.54 to -0.22 g/l], P<0.001). In the subgroup analyses by therapy duration, plasma fibrinogen concentrations declined significantly in the long-term (≥1 month) CPAP therapy subgroup (WMD = -0.33 g/l, 95% CI [-0.49 to -0.16 g/l], P<0.001) but not in the short-term (<1 month) CPAP therapy subgroup (WMD = -0.84 g/l, 95% CI [-1.70 to 0.03 g/l], P=0.058). Moreover, in patients with long-term CPAP therapy duration, plasma fibrinogen levels decreased with good CPAP compliance (≥4 h/night) (WMD = -0.37 g/l, 95% CI [-0.55 to -0.19 g/l], P<0.001) but not with poor CPAP compliance (<4 h/night) (WMD = 0.12 g/l, 95% CI [-0.09 to 0.33 g/l], P=0.247). CONCLUSION: Long-term CPAP treatment with good compliance can reduce the plasma fibrinogen levels in patients with OSA.

Comparison of clinical, laboratory, and radiological characteristics between SARS-CoV-2 infection and community-acquired pneumonia caused by influenza virus: A cross-sectional retrospective study.

Coronavirus disease 2019 (COVID-19) is the most important global public health issue that we currently face. We aimed to explore the clinical features of patients with COVID-19 and compared them with those of hospitalized community-acquired pneumonia (CAP) patients caused by influenza virus during the same period.From Jan 1, to Mar 4, 2020, patients with COVID-19 or CAP caused by influenza virus who were admitted to the First Affiliated Hospital of Xiamen University were consecutively screened for enrollment.A total of 35 COVID-19 patients and 22 CAP patients caused by influenza virus were included in this study. Most of COVID-19 patients had characteristics of familial clustering (63%), however, in the other group, there was no similar finding. The percentages of patients with a high fever (the highest recorded temperature was ≥39.0°C; 11% vs 45% [COVID-19 vs CAP groups, respectively]), dyspnea (9% vs 59%), leukocytosis (3% vs 32%), elevated C-reactive protein concentrations (>10 mg/L, 48% vs 86%), elevated procalcitonin levels (>0.1 ng/ml, 15% vs 73%), PaO2/FiO2 <200 mm Hg (4% vs 22%), and infiltration on imaging (29% vs 68%) in the COVID-19 group were less than those same indices in the hospitalized CAP patients caused by influenza virus. Ground-glass opacity with reticular pattern (63%) and interlobular septal thickening (71%) in chest CT were commonly observed in the COVID-19 group.COVID-19 and CAP caused by influenza virus appear to share some similarities in clinical manifestaions but they definitely have major distinctions. Influenza infection remains a health problem even during COVID-19 pandemic.

Association between serum adiponectin concentrations and chronic obstructive pulmonary disease: a meta-analysis.

BACKGROUND: Adiponectin has been implicated to play a role in the pathophysiology of chronic obstructive pulmonary disease (COPD). Many studies have assessed serum adiponectin concentrations in COPD patients. However, results from different reports were not consistent. To assess the association of serum adiponectin concentrations and COPD, a meta-analysis was performed. METHODS: PubMed, Embase, Web of Science and Cochrane Library were searched for eligible studies. Data were extracted, and then standard mean differences (SMDs) and 95% confidence intervals (CI) were calculated. RESULTS: Thirteen studies involving a total of 1131 cases and 689 controls were included in this meta-analysis. Combined data indicated that the serum adiponectin levels were higher in COPD patients than those in controls (SMD: 1.09, 95% CI [0.73-1.45], P < 0.001). In the subgroup analyses by disease period, there were similar results in stable COPD patients (SMD: 0.77, 95% CI [0.47-1.07], p <0.001; I2 = 83.9%, P < 0.001), AECOPD patients (SMD: 2.51, 95% CI [0.71-4.30], P = 0.006; I2 = 95.2%, P < 0.001) and mixed COPD patients (SMD: 1.21, 95% CI [0.67-1.75], P < 0.001). Furthermore, the serum adiponectin levels were higher in AECOPD patients than those in stable COPD patients (SMD: 1.06, 95% CI [0.13-1.99], P = 0.026). CONCLUSIONS: This meta-analysis indicates that patients with COPD have higher serum adiponectin concentration than healthy controls.

Circulating fibrinogen levels are elevated in patients with obstructive sleep apnea: a systemic review and meta-analysis.

OBJECTIVE: Fibrinogen is believed to play a role in the pathophysiology of obstructive sleep apnea (OSA) and many studies have assessed circulating fibrinogen concentrations in OSA patients. However, the results from these studies were not consistent. To assess the association of circulating fibrinogen levels and OSA, a meta-analysis was performed. METHODS: PubMed, Embase and Web of Science databases were searched for eligible studies. Data were extracted, and then weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated. RESULTS: A total of 25 studies involving 1480 cases and 2312 controls were included in this meta-analysis. Combined data indicated that the circulating fibrinogen levels were higher in OSA patients than in controls (WMD: 0.38 g/L, 95% CI [0.29-0.47 g/L], p < 0.001; I2 = 80.3%, p < 0.001). In the subgroup analyses by disease severity, there were similar results in mild-moderate OSA patients (WMD: 0.27 g/L, 95% CI [0.14-0.41 g/L], p < 0.001; I2 = 29.3%, p = 0.185) and severe OSA patients (WMD: 0.54 g/L, 95% CI [0.28-0.79 g/L], p < 0.001; I2 = 65.9%, p = 0.012). Furthermore, in another subgroup analysis, the circulating fibrinogen levels were higher in OSA patients than those in controls who were matched for important potential confounders (WMD: 0.41 g/L, 95% CI [0.21-0.60 g/L], p < 0.001; I2 = 62.0%, p = 0.003). CONCLUSIONS: This systematic review and meta-analysis reveals that circulating fibrinogen levels are elevated in patients with OSA.

Serum C-reactive protein level in COPD patients stratified according to GOLD 2011 grading classification.

BACKGROUND AND OBJECTIVE: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 grading classification has been used to evaluate the severity of patients with chronic obstructive pulmonary disease (COPD). However, little is known about the relationship between the systemic inflammation and this classification. We aimed to study the relationship between serum CRP and the components of the GOLD 2011 grading classification. METHODS: C-reactive protein (CRP) levels were measured in 391 clinically stable COPD patients and in 50 controls from June 2, 2015 to October 31, 2015 in the First Affiliated Hospital of Xiamen University. The association between CRP levels and the components of the GOLD 2011 grading classification were assessed. RESULTS: Correlation was found with the following variables: GOLD 2011 group (0.240), age (0.227), pack year (0.136), forced expiratory volume in one second % predicted (FEV1%; -0.267), forced vital capacity % predicted (-0.210), number of acute exacerbations in the past year (0.265), number of hospitalized exacerbations in the past year (0.165), British medical Research Council dyspnoea scale (0.121), COPD assessment test score (CAT, 0.233). Using multivariate analysis, FEV1% and CAT score manifested the strongest negative association with CRP levels. CONCLUSIONS: CRP levels differ in COPD patients among groups A-D based on GOLD 2011 grading classification. CRP levels are associated with several important clinical variables, of which FEV1% and CAT score manifested the strongest negative correlation.

[Relationship between AKAP95, cyclin E1, cyclin D1, and clinicopathological parameters in lung cancer tissue].

OBJECTIVE: To investigate the correlation between expression of A-kinase anchoring protein 95 (AKAP95) and protein expression of cyclin E1 and cyclin D1 in lung cancer tissue. METHODS: Fifty-one cases of lung cancer were included in the study. The protein expression of AKAP95, cyclin E1, and cyclin D1 were measured by immunohistochemistry. RESULTS: The protein expression of cyclin E1 in lung cancer tissues was significantly higher than that in para-cancerous tissues (positive rate: 75.56%vs 20%, P < 0.01); its expression showed no relationship with histopathological type, lymph node metastasis, and cellular differentiation (P > 0.05). The protein expression of cyclin D1 in lung cancer tissues was higher than that in para-cancerous tissues (positive rate: 69.39% vs 14.29%); its expression showed a significant relationship with histopathological type (P < 0.05). The expression of AKAP95 was correlated with the protein expression of cyclin E1 and cyclin D1 in lung cancer tissues (P < 0.01). CONCLUSION: Cyclin E1 and cyclin D1 are highly expressed in lung cancer tissue, suggesting that they play an important role in the development and progression of lung cancer. The protein expression of cyclin E1 has no relationship with cellular differentiation, lymph node metastasis, and histopathological type of lung cancer, and the protein expression of cyclin D1 has a significant relationship with histopathological type. The expression of AKAP95 is correlated with the protein expression of cyclin E1 and cyclin D1 in lung cancer tissue.

Antiproliferation and apoptosis induced by tamoxifen in human bile duct carcinoma QBC939 cells via upregulated p53 expression.

Tamoxifen (TAM) is a nonsteroidal antiestrogen that has been used in the treatment of breast cancer for over 30years. Recently, it was shown that TAM also has efficacy on gastrointestinal neoplasms such as hepatocarcinoma and pancreatic carcinoma, and that the chemopreventive activities of TAM might be due to its abilities to inhibit cell growth and induce apoptosis. In the present study, we investigated the effects of tamoxifen on growth and apoptosis in the human bile duct carcinoma (BDC) cell line QBC939 using MTT assay, inverted microscopy, fluorescence microscopy, transmission electron microscopy, classic DNA fragmentation agarose gel electrophoresis assay, PI single- and FITC/PI double-staining flow cytometry, and Western blotting. Our data revealed that TAM could significantly inhibit growth and induce apoptosis in QBC939 cells. Increased expression of p53 was observed in TAM-treated cells, indicating that p53 might play an important role in TAM-induced apoptosis in QBC939 cells. These results provide significant insight into the anticarcinogenic action of TAM on BDC.